Amorphous Drug–Polymer Salt with High Stability under Tropical Conditions and Fast Dissolution: The Case of Clofazimine and Poly(acrylic acid)

We report that the
stability of amorphous clofazimine (CFZ) against
crystallization is vastly improved by salt formation with a polymer
without sacrificing dissolution rate. A simple slurry method was used
to produce the amorphous salt of CFZ with poly­(acrylic acid) (PAA)
at 75 wt % drug loading. The synthesis was performed under a mild
condition suitable for thermally unstable drugs and polymers. Salt
formation was confirmed by visible spectroscopy and glass temperature
elevation. The amorphous salt at 75 wt % drug loading is remarkably
stable against crystallization at 40 °C and 75% RH for at least
180 days. In contrast, the amorphous solid dispersion containing the
un-ionized CFZ dispersed in poly­(vinylpyrrolidone) crystallized in
1 week under the same condition. The high stability of the amorphous
drug–polymer salt is a result of the absence of a drug–polymer
crystalline structure, reduced driving force for crystallizing the
free base, and reduced molecular mobility. Despite the elevated stability,
the amorphous drug–polymer salt showed fast dissolution and
high solution concentration in two biorelevant media (SGF and FaSSIF).
Additionally, the amorphous CFZ–PAA salt has improved tabletability
and powder flow relative to crystalline CFZ. The CFZ–PAA example
suggests a general method to prepare amorphous drugs with high physical
stability under tropical conditions and fast dissolution.